Serotonin (5HT), released upon stimulation of structures in the brainstem and in the midbrain, inhibits the activity of spinothalamic tract (STT) projection cells in the spinal cord and produces analgesia. This descending serotonergic control is of considerable interest because of its potential implication in the clinical treatment of pain. The long-term objective of this proposal is to elucidate the cellular mechanism underlying the 5HT actions on spinal cord neurons. Our goals here are (1) to determine, at the cellular level, how different 5HT receptor subtypes participate in modulating the activity of STT neurons and interneurons in the substantia gelatinosa (SG), (2) to define the role of 5HT in modulating the activity of these neurons in arthritic rats. To accomplish these goals, we will use the patch recording technique to study the 5HT effects on the voltage-dependent and synaptic currents in labeled SG and STT cells in rat cervical slices. Two hypotheses will be tested. HYPOTHESIS 1: 5HT actions on dorsal horn neurons depends on receptor subtypes and their pre- and post-synaptic locations. The effects of 5HT on stalked and islet cells in the SG and on STT neurons are different. To test the hypothesis, we will determine if the specific 5HT receptor subtypes are located on the pre- or post-synaptic cells and how different 5HT receptor subtypes work together to modulate the activity of labeled STT neurons. HYPOTHESIS 2: The sensitization of NMDA receptors and the presumed loss of 5HT inhibitory control contribute to the hyperactivity of dorsal horn neurons in arthritic rats. To test this hypothesis, we will determine (a) if the NMDA responses are enhanced in SG and STT neurons of arthritic rats and (b) if the enhancement results from the activation of protein kinase C (PKC) in the cells. The effect of 5HT on the excitability of SG and STT cells in arthritic rats will also be determined. These studies will establish the roles 5HT receptors have in nociceptive processing and hyperalgesia, and will help to develop new therapeutic agents for treating arthritic and hyperalgesic patients.